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Figure 1. KDM6A loss links genomic instability, immunometabolic remodeling and therapeutic response in bladder cancer. (I) KDM6A promotes chromatin accessibility by inhibiting repressive H3K27me3 and increasing the transcription of DNA repair genes. Increased deposition of H3K27me3 and decreased deposition of H3K4me3 at DNA repair gene promoters due to KDM6A loss downregulate the expression of MSH2, MSH6, and EXO1. These alterations contribute to DNA repair deficiency, DNA damage, chromosomal instability, replication stress, as well as the formation of micronuclei and eccDNA; (II) Genomic instability might enhance the immunogenicity and immune detection of tumors, whereas KDM6A loss is also associated with reduced glycolysis, glycolytic gene expression, glucose uptake, and lactate production; (III) These changes distinguish two separable therapeutic consequences of KDM6A loss. The genomic-instability arm associated with eccDNA may favour amplification of candidate resistance loci and contribute to cisplatin resistance. Conversely, DNA repair defects and lactate-dependent immunometabolic rewiring may confer sensitivity to immune checkpoint blockade (ICB), especially PD-1/PD-L1 blockade, due to decreased Treg-cell histone lactylation, which limits the expansion of PD-1^hi Tregs and increases the CD8⁺ T-cell/Treg ratio. Created in BioRender. Zhang H (2026) https://BioRender.com/fnuhatw.